International patent applications US03/12929, filed Apr. 25, 2003, and US03/13042, filed Apr. 25, 2003, disclose tetrahydropyranyl cyclopentyl tetrahydropyridopyridine compounds. These compounds are useful for the treatment of diseases or conditions of humans or other species which can be treated with inhibitors, modulators or promoters of chemokine receptor function. Such diseases or conditions include those mentioned in the referenced applications.
((1R,3S)-3-Isopropyl-3-{[3-(trifluoromethyl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl]carbonyl}cyclopentyl)[(3S,4S)-3-methoxytetrahydro-2H-pyran-4-yl]amine, 1:
is a potent CCR-2 inhibitor. The laboratory preparation of compound 1, including the laboratory preparation of certain intermediates and precursors employed to in the synthesis of compound 1 is described in International patent applications US03/12929 and US03/13042.
Prior techniques for synthesizing compound 1 were inefficient and time consuming, and thus expensive from the standpoint of production. The synthesis of the naphthyridine building block, for example, comprised nine separate steps and required the use of several expensive reagents, hampering the efficiency of the overall synthetic process. Similarly, the synthesis of the cyclopentene building block resulted in a high proportion of undesirable stereoisomers. Other aspects of the synthesis were likewise inefficient, expensive, and/or not amenable to commercial production. Previously synthesized hydrochloride salts of compound 1, moreover, displayed less than ideal solubility, handling (e.g., hydroscopicity) and other properties. Thus, there remains a need for an improved synthetic route to compound 1 that is amenable to large scale production formulation, storage and distribution. There also remains a need to develop improved salt forms of compound 1.